Inês Dias

Neurodegenerative disorders (NDs), such as Alzheimer’s and Parkinson’s diseases (AD and PD), despite having different main neuropathological hallmarks, share several interconnected aetiologic mechanisms and lack effective disease-modifying treatments. The multifactorial nature of these diseases has encouraged the development of new drugs such as multi-target-directed ligands (MTDLs). In this work, an anti-AD drug (rivastigmine, RIV) was fused and conjugated with a series of antioxidant scaffolds to obtain a small library of RIV–antiox hybrids. In addition to inhibitory activity towards both cholinesterases, these hybrids exhibited radical scavenging activity, inhibition of Aβ aggregation, and neuroprotection against cell death induced in AD models. The relevant anti-AD properties already found for these hybrids challenged us to also assess their capacity to modulate and interfere with ROS-associated harmful dysfunctions, namely in the dysregulation of biometal ions (Fe³⁺, Cu²⁺, and Zn²⁺) and upregulation of monoamine oxidases (MAOs). In particular, the capacity of the hybrids for metal chelation and inhibition of Cu-induced Aβ aggregation and MAO isoforms was evaluated, as well as their neuroprotection capacity in cell models of PD. Overall, some of these RIV hybrids appear as lead compounds for the development of novel multifunctional agents against NDs.

The development of gadolinium-based magnetic resonance imaging (MRI) contrast agents (CAs) is a highly challenging and demanding research field in metal-coordination medicinal chemistry. The recognized high capacity of hydroxypyridinone (HOPO)-based compounds to coordinate Gd (III) led us to evaluate the set of physic–chemical–biological properties of a new Gd (III) complex with a hexadentate tripodal ligand (H₃L) containing three 3,4-HOPO chelating moieties attached to an anchoring cyclohexane backbone. In particular, the thermodynamic stability constants of the complex were evaluated by potentiometry, showing the formation of a highly stable (1:1) Gd-L complex (log β_GdL = 26.59), with full coordination even in an acid-neutral pH under the experimental conditions used. Molecular simulations of the Gd (III) complex revealed a minimum energy structure with somewhat-distorted octahedral geometry, involving full metal hexa-coordination by the three bidentate moieties of the ligand arms, indicating that an extra water molecule should be coordinated to the metal ion, an important feature for the CAs (and the required enhancement of water proton relaxivity). In vivo biodistribution studies with the ⁶⁷Ga complex, as a surrogate of the corresponding Gd complex, showed in vivo stability and rapid excretion from the animal body. Though deserving further investigation, these results may give an input on future perspectives towards new MRI diagnostic agents.

The development of gadolinium-based magnetic resonance imaging (MRI) contrast agents (CAs) is a highly challenging and demanding research field in metal-coordination medicinal chemistry. The recognized high capacity of hydroxypyridinone (HOPO)-based compounds to coordinate Gd(III) led us to evaluate a set of physic-chemical-biological properties of a new Gd(III)-complex with an hexadentate tripodal ligand (H3L), containing three 3,4-HOPO chelating moieties attached to an anchoring cyclohexane backbone. In particular, the thermodynamic stability constants of the complex were evaluated by potentiometry, showing the formation of a high stable (1:1) Gd-L complex (log GdL = 26.59), with full coordination even in acid-neutral pH conditions. Molecular simulations of the Gd(III) complex revealed a minimum energy structure with somehow distorted octahedral geometry, involving full metal hexa-coordination by the three bidentate moieties of the ligand arms, indicating that extra water molecules should be coordinated to the metal ion, an important feature for the CAs (required enhancement of water proton relaxivity). In vivo biodistribution studies with the 67Ga complex, as surrogate of the corresponding Gd complex, showed in vivo stability and rapid excretion from the animal body. Though deserving further investigation, these results may give an input on future perspectives towards new MRI diagnostic agents.

Alzheimer’s disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search for new multitarget drugs. Therefore, following a multitarget approach, nine rivastigmine–indole (RIV-IND) hybrids (5a1-3, 5b1-3, 5c1-3) were designed, synthesized and evaluated for their multiple biological properties and free radical scavenging activity, as potential multitarget anti-AD drugs. The molecular docking studies of these hybrids on the active center of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) suggest their capacity to act as dual enzyme inhibitors with probable greater disease-modifying impact relative to AChE-selective FDA-approved drugs. Compounds 5a3 (IC₅₀ = 10.9 µM) and 5c3 (IC₅₀ = 26.8 µM) revealed higher AChE inhibition than the parent RIV drug. Radical scavenging assays demonstrated that all the hybrids containing a hydroxyl substituent in the IND moiety (5a2-3, 5b2-3, 5c2-3) have good antioxidant activity (EC₅₀ 7.8–20.7 µM). The most effective inhibitors of Aβ₄₂ self-aggregation are 5a3, 5b3 and 5c3 (47.8–55.5%), and compounds 5b2 and 5c2 can prevent the toxicity induced by Aβ_1-42 to cells. The in silico evaluation of the drug-likeness of the hybrids also showed that all the compounds seem to have potential oral availability. Overall, within this class of RIV-IND hybrids, 5a3 and 5c3 appear as lead compounds for anti-AD drug candidates, deserving further investigation.